The use of antipsychotic drugs for the treatment of schizophrenia-like symptoms is often associated with adverse side effects such as motor disturbances, weight gain and sexual dysfunction. Hence, there is a continuous need for alternative well-tolerated antipsychotic drugs.
It has been known since long that different components of the plant Cannabis sativa (cannabis) have pharmacological activity. Cannabis contains various cannabinoids, two of which have almost opposing actions. Δ9-Tetrahydrocannabinol (THC), which is the most abundant cannabinoid in smoked cannabis, is known to be a psychotomimetic component. In contrast, cannabidiol (CBD), which is another major cannabinoid found in some strains of cannabis, has been found to have antipsychotic properties.
The antipsychotic properties of CBD have been investigated. Publications describing studies in which schizophrenic patients were treated with CBD indicate that CBD is a well-tolerated alternative drug for the treatment of for example schizophrenia.
CBD is a lipophilic substance that is not soluble in water. It is soluble in ethanol (36 mg/ml) and dimethylsulfoxide DMSO (60 mg/ml). CBD has a melting point of about 66° C.
Bioavailability of pharmaceutical substances taken perorally, first of all, depends on the extent to which the pharmaceutically active substance is absorbed from the intestinal environment across the intestinal mucosa. Lipophilic pharmaceutical substances are generally poorly absorbed from the intestinal environment, inter alia because of their poor solubility and/or dispersibility in water.
Bioavailability of a pharmaceutical substance taken perorally furthermore depends on the susceptibility of the substance to the so-called first pass effect. Substances absorbed from the intestine, before being distributed throughout the body, have to pass the liver first where they may be metabolized immediately. CBD is generally assumed to be rather susceptible to first-pass liver metabolization.
Oral bioavailability of CBD is low and unpredictable (S. Zhornitsky, S. Potvin, Pharmaceuticals (2012) 5, 529-552). In addition, CBD is an unstable drug (A. J. Poortman, H. Huizer, Forensic Science International (1999) 101, 1-8).
Therapeutic applications of CBD have been described in several publications.
F. M. Leweke et al. (Transl. Psychiatry (2012) 2, e94) describe the treatment of humans of age between 18 and 50 years old suffering from acute paranoid schizophrenia by daily administering 200 to 800 mg CBD or a similar dose of the potent antipsychotic drug amisulpride.
A. W. Zuardi et al. (Braz. J. Med. Biol. Res. (2006) 39, 421-429 and Journal of Psychopharmacology (2006) 20(5), 683-686) describe a case study in which a schizophrenic patient received high doses of CBD (dissolved in oil) up to 1500 mg/day for 4 weeks and showed significant improvement during CBD treatment while a worsening was observed when the administration was interrupted. In another case study, a patient with a diagnosis of schizophrenia was administered doses of CBD, starting with 40 mg/day for 5 days, with the dose being doubled every 5 days up to 1280 mg/day during a period of about 4 weeks. A trend for symptom improvement was observed at a dose of 1280 mg/day.
US 2011/038958 relates to a method for treatment or prevention of psychosis or a psychotic disorder. The method of treatment comprises administering to a patient a therapeutically effective amount of tetrahydrocannabivarin (THCV) and/or CBD. US 2011/038958 describes an experiment in which mice received once daily oral doses of 0.3 and 3 mg/kg CBD in combination with pure THCV.
WO 2008/033024 describes dosage units for sublingual, buccal or oral administration of water-insoluble pharmaceutically active substances. CBD is mentioned as an example of water-insoluble pharmaceutically active substances. Example 1 describes the preparation of a monophasic microgranulate comprising the cannabinoid Δ-9-tetrahydrocannabinol, and sucrose monolaurate in a weight ratio of 1:15 using a dry granulation process. Example 3 of this patent application describes the manufacture of a tabletting powder for direct compression using 5 g of the microgranulate obtained from Example 1 and 17 g of other components including 5 g of lactose and the compression to 7 mm tablets with a total weight of 60 mg. Example 6 describes the preparation of tablets containing 61 mg of a microgranulate, 180 mg lactose and 10 mg of other excipients, said microgranulate being composed of Δ-9-tetrahydrocannabinol (THC), sucrose monolaurate and xylitol. The microgranulate was prepared by successively dispersing sucrose monolaurate and xylitol into molten xylitol, followed by cooling and grinding.
WO 02/064109 describes a pharmaceutical formulation for use in administration of a lipophilic medicament via a mucosal surface, which formulation comprises at least one lipophilic medicament and at least one self emulsifying agent. Also described are pharmaceutical formulations in the form of a gel or a compressed tablet for administration of a lipophilic medicament via the sublingual and/or buccal mucosa. Among the lipophilic medicaments mentioned in WO 02/064109 A2 are THC and mixtures of THC and CBD. The pharmaceutical formulations are intended for the treatment of a variety of diseases among which are multiple sclerosis, spinal cord injury, peripheral neuropathy and other neurogenic pain. Example 6 of the patent application describes the preparation of a tablet for buccal or sublingual administration by dissolving glyceryl monostearate, polysorbate 80, ascorbyl palmitate and α-tocopherol and THC in alcohol, spraying the alcoholic solution onto a powder mix consisting of lactose and soluble starch, evaporating the alcohol, dusting the resulting granulate with talc and compressing to a target tablet weight of 101 mg.
WO 2009/087351 describes the use of one or more phyto-cannabinoids, including CBD, with one or more anti-psychotic medicaments in the manufacture of a pharmaceutical formulation for use in the prevention or treatment of psychosis or a psychotic disorder, wherein the one or more phyto-cannabinoids are administered separately, sequentially or simultaneously to the one or more anti-psychotic medicaments.
WO 2012/033478 describes an oral dosage form of cannabinoids, among which CBD, in a self-emulsifying system operable to avoid hepatic first pass metabolism, said oral dosage form comprising:                1-90 wt. % of a pharmacologically active form of cannabinoids;        15-85 wt. % of one or more triglycerides;        15-85 wt. % of one or more mixed glycerides; and        5-90 wt. % of a surfactant which promotes self-emulsification.        
It is an object of the present invention to provide a dosage unit for peroral administration of CBD that combines high and predictable bioavailability with excellent stability. It is a further object of the invention to provide dosage units for peroral administration of CBD that can conveniently be used in the treatment of psychosis disorders or anxiety disorders.